This project is designed to investigate the clinical susceptibility of breast cancer and non-Hodgkin's lymphoma (NHL) to graft-versus-tumor (GVT) effects and to develop methods to augment GVT effects to improve the efficacy of alloHSCT in these two diseases, which were specifically selected based upon their clinical significance and research interests in the ETIB. Breast Cancer - We first investigated in protocol 00-C-0119 whether allogeneic lymphocytes could elicit a clinical GVT effect in breast cancer in the setting of reduced-intensity alloHSCT, based on ETIB murine studies. To help us distinguish GVT effects from the anti-tumor effects of the conditioning regimen, the trial design incorporated a strategy of T cell depleting the allograft and then delaying the administration of donor lymphocytes to a time distant from the effects of cytotoxic chemotherapy. This trial provided several important observations. First, tumor regressions occurred late post-alloHSCT, strongly suggesting that an immune-associated GVT effect against metastatic breast cancer exists. Second, the GVT effect was observed only after establishment of complete donor lymphoid chimerism. Third, responses were observed in disease that had progressed after chemotherapy, suggesting chemotherapy-sensitive disease was not an absolute requirement for a GVT effect. Fourth, the GVT effect was relatively tenuous, as it was abrogated when steroids were used for the treatment of GVHD. Based on these results we have initiated a clinical trial, 04-C-0131, utilizing graft engineering with Th2/Tc2 cells in an effort to facilitate rapid lymphoid donor engraftment and mediate GVT effects with reduced GVHD. To further augment the GVT effect, we will investigate allogeneic tumor-infiltrating lymphocytes in patients who have less than complete responses to alloHSCT. For patients who do not initially respond to alloHSCT, we will be incorporating a tumor vaccine strategy (PANVAC) into our post-transplant DLI program in order to improve immune response to tumor antigens. Ultimately our intent is to incorporate the individual strategies currently under investigation that show promise into a single treatment approach to improve the response rate and durability of response to allogeneic adoptive cellular therapy in metastatic breast cancer.Non-Hodgkin's Lymphoma - We chose to specifically focus efforts upon chemo-refractory NHL in which the efficacy of reduced-intensity alloHSCT is limited. To potentiate the GVT effect in NHL, we have purposely attempted to achieve rapid, complete donor chimerism through targeted immune-depletion, as described above, using a novel induction regimen for NHL, EPOCH-F/R. In protocols 99-C-0143 and 03-C-0077, response to EPOCH-F/R correlated with outcome post-alloHSCT. In these trials we observed that patients with stable disease, who would otherwise be considered to have chemo-refractory NHL, obtained durable complete remissions with this approach. This finding suggests that failure to respond to salvage chemotherapy should not be considered an absolute contraindication to reduced-intensity alloHSCT for NHL. Ongoing and future efforts focus on optimizing the anti-tumor effects of EPOCH-F/R and on achieving minimal disease states for NHL prior to reduced-intensity alloHSCT. In addition, we are investigating in protocol 00-C-0201 whether vaccination of normal allogeneic stem cell donors with patient-derived Id-specific vaccine will generate id-specific immunity which will be passively transferred to the recipient after alloHSCT, thereby reducing the risk of response relapse in multiple myeloma. The results of this latter study could potentially be more broadly applied to our studies in NHL and breast cancer.